Andre H. Goy, MD: Generally speaking, how has the treatment paradigm of large cell lymphoma shifted in recent years? In particular, how many patients develop relapsed/refractory disease?

Andrew Ip, MD: It’s probably easier to answer the second question. There are already great statistics from the post-rituximab era from the early 2000s that we’re still not perfect. The 5-year PFS [progression-free survival] rates are usually around 65% to 70% for most large databases and many of the large trials that we know through the early 2010s. So, it seems that about 30% would relapse in general or potentially have refractory disease. And further, just like we talked about in mantle cell lymphoma, it’s a very biologically heterogeneous tumor as well for DLBCL [diffuse large B-cell lymphoma]. The relapse rates for someone with a high-grade or double-hit lymphoma are much higher, probably around upwards of 70%.

So certainly, we’re not perfect, and I think that is why, at least for me, who’s practiced lymphoma independently now at Hackensack University Medical Center in Hackensack, New Jersey, for the last 3 or 4 years, and also trained in this kind of CAR [chimeric antigen receptor] T-cell trial era for 4 to 6 years before that, the change in treatment paradigms for large B-cell lymphoma has been remarkable now that we have CAR T-cell therapy and things like bispecifics and other new treatments besides just chemotherapy and chemoimmunotherapy with rituximab alone. In the last 2 years, especially for second-line treatment, the paradigm has greatly changed with results from ZUMA-7 [NCT03391466] and TRANSFORM [NCT03575351], and to use CAR T-cell therapy early on in the second-line setting.

Andre H. Goy, MD: Thank you for this. The standard of care has been by default since 2000 R-CHOP [rituximab plus cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone] times 6, and we have tried many efforts to do better. Where do we stand on who should get R-CHOP and who should not get R-CHOP?

Andrew Ip, MD: As you know, at Hackensack, not many of our patients who we think are high risk, which you could define high risk in different ways. You could use IPI [International Prognostic Index] score, which we know doesn’t technically capture all of the biological risk, but certainly has clinical characteristics. You could use things that include the biology, like double hit status or maybe high Ki-67, or the presence of a TP53 mutation expression. Or for us at Hackensack, we’ve been using a lot more genomic profiling of tumors to understand maybe the high chromosomal structural alterations within a tumor or just understanding better their pathology on these more specific and sensitive testing. As a lymphoma physician, I don’t think R-CHOP is going to cure these higher-risk patients. Again, high risk can be defined in different ways, but I would define a double expresser as being high risk, and double hits, a high Ki-67, or just very bulky clinical presentation, which usually may include extranodal sites. If there’s bone involvement, liver involvement, involvement near the spine, or involving the spine, those would be high risk in my mind, and I think would deserve dose-intense treatment.

We’ve had different trials report out of dose-adjusted R-EPOCH [rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride] vs R-CHOP from the CLGB [Cancer and Leukemia Group B] and Alliance team. There was maybe a signal for non-GC [non-germinal center], but there were a lot of issues with the logistics of the trial. And so at least for me, it leaves a lot of desire to have better treatments than R-CHOP. But in the clinical trials that have been performed in the last 20 years, it seems that R-CHOP still always is either noninferior or maybe safer than some of the dose-intense treatments. But I think some of that speaks to a lot of centers maybe not being comfortable with giving hyper-CVAD [cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone].

As you mentioned, the University of Texas MD Anderson Cancer Center in Houston, Texas, does a lot of things for mantle cells. They also give a lot of hyper-CVAD dose-intense treatment for high-grade lymphomas, and they’re very comfortable with that. That’s where I trained as well, we gave a lot of hyper-CVAD. And of course, here at Hackensack, we give a lot more dose-intense treatment than other sites. There is still that open question and it’s been hard to answer, but in the last few years, now that we have other drugs to consider, like bispecifics, CAR T-cell therapy, even some of the small molecules, we can try to think about how to better deliver frontline treatment for DLBCL. And certainly, there are some trial ideas that should be considered as well.

Andre H. Goy, MD: As you mentioned, for the last 2 decades, we have tried to do better than R-CHOP. And although we have very appealing data in phase 2 that provided rationale every time, the phase 3 didn’t pan out. The only trial that has shown a clinical benefit is the pola-R-CHP [polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone] [NCT03274492], and it was just approved. Maybe you can comment on the reason for this benefit. What do you think about it?

Andrew Ip, MD: Polatuzumab is an anti-CD79 antibody with an MMAE [monomethyl auristatin E], very similar to the mechanism of something like vincristine. But it’s essentially a chemotherapy-targeting agent, and it’s replacing vincristine. POLARIX [NCT03274492] was a phase 3 international trial. When I was at Emory [University School of Medicine in Atlanta, Georgia], we were enrolling patients in this trial, and it showed a PFS benefit. That was reported in the New England Journal of Medicine. The PFS benefit was somewhere in the 5% to 6% range. It was not striking, but it certainly was statistically significant, given they had several hundred patients on the trial. But I don’t think it necessarily gave us that oomph, at least for me, that it’s much better than maybe R-CHOP alone, or even if you gave more dose-intense treatments, because they only compared it to R-CHOP alone. And at least for our sites, we use polatuzumab in the relapse setting. Pola-BR [polatuzumab vedotin, bendamustine, obinutuzumab] is approved for relapsed lymphoma.

When we talk about getting patients to potentially treatments like CAR T-cell therapy and others, we need to bridge them with treatments. Polatuzumab is often a good drug to bridge because it’s well tolerated, and it still is some chemotherapy. We talked about, what is the best sequence of care? What is the best drug to give right now? I’m not sure that the POLARIX study is moving the needle for me in terms of replacing R-CHOP, because certainly we have other great options in the second-line setting now.

Andre H. Goy, MD: There was no benefit in survival and then maybe there was a better in—

Andrew Ip, MD: There’s a slight PFS benefit, not an OS [overall survival] benefit.

Andre H. Goy, MD: But it only showed that it was a tremendous effort, and we tried this in many compounds.

Transcript edited for clarity.